Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing
Runs in the Family
The power to detect mutations involved in disease by genome sequencing is enhanced when combined with the ability to discover specific mutations that may have arisen between offspring and parents. Roach et al. (p. 636, published online 10 March) present the sequence of a family with two offspring affected with two genetic disorders: Miller syndrome and primary ciliary dyskinesia. Sequence analysis of the children and their parents not only showed that the intergenerational mutation rate was lower than anticipated but also revealed recombination sites and the occurrence of rare polymorphisms.
Abstract
We analyzed the whole-genome sequences of a family of four, consisting of two siblings and their parents. Family-based sequencing allowed us to delineate recombination sites precisely, identify 70% of the sequencing errors (resulting in > 99.999% accuracy), and identify very rare single-nucleotide polymorphisms. We also directly estimated a human intergeneration mutation rate of ~1.1 × 10−8 per position per haploid genome. Both offspring in this family have two recessive disorders: Miller syndrome, for which the gene was concurrently identified, and primary ciliary dyskinesia, for which causative genes have been previously identified. Family-based genome analysis enabled us to narrow the candidate genes for both of these Mendelian disorders to only four. Our results demonstrate the value of complete genome sequencing in families.
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References and Notes
1
Drmanac R., et al., Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science 327, 78 (2010).
2
Roach J. C., Boysen C., Wang K., Hood L., Pairwise end sequencing: A unified approach to genomic mapping and sequencing. Genomics 26, 345 (1995).
3
Watterson G. A., On the number of segregating sites in genetical models without recombination. Theor. Popul. Biol. 7, 256 (1975).
4
Materials and methods are available as supporting material on Science Online.
5
Donnelly K. P., The probability that related individuals share some section of genome identical by descent. Theor. Popul. Biol. 23, 34 (1983).
6
Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S., Parametric and nonparametric linkage analysis: A unified multipoint approach. Am. J. Hum. Genet. 58, 1347 (1996).
7
Abecasis G. R., Cherny S. S., Cookson W. O., Cardon L. R., Merlin—Rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97 (2002).
8
Petkov P. M., Broman K. W., Szatkiewicz J. P., Paigen K., Crossover interference underlies sex differences in recombination rates. Trends Genet. 23, 539 (2007).
9
Chimpanzee Sequencing and Analysis Consortium, Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69 (2005).
10
Nachman M. W., Crowell S. L., Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297 (2000).
11
Haile-Selassie Y., Late Miocene hominids from the Middle Awash, Ethiopia. Nature 412, 178 (2001).
12
Haile-Selassie Y., Asfaw B., White T. D., Hominid cranial remains from upper Pleistocene deposits at Aduma, Middle Awash, Ethiopia. Am. J. Phys. Anthropol. 123, 1 (2004).
13
Haile-Selassie Y., Suwa G., White T. D., Late Miocene teeth from Middle Awash, Ethiopia, and early hominid dental evolution. Science 303, 1503 (2004).
14
Deino A. L., Tauxe L., Monaghan M., Hill A., 40Ar/(39)Ar geochronology and paleomagnetic stratigraphy of the Lukeino and lower Chemeron Formations at Tabarin and Kapcheberek, Tugen Hills, Kenya. J. Hum. Evol. 42, 117 (2002).
15
Brunet M., et al., A new hominid from the Upper Miocene of Chad, Central Africa. Nature 418, 145 (2002).
16
Chen F. C., Li W. H., Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am. J. Hum. Genet. 68, 444 (2001).
17
Burgess R., Yang Z., Estimation of hominoid ancestral population sizes under bayesian coalescent models incorporating mutation rate variation and sequencing errors. Mol. Biol. Evol. 25, 1979 (2008).
18
Takahata N., Relaxed natural selection in human populations during the Pleistocene. Jpn. J. Genet. 68, 539 (1993).
19
J. D. Wall, Estimating ancestral population sizes and divergence times. Genetics 163, 395 (2003). [Abstract/Free Full Text]
20
Kondrashov A. S., Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum. Mutat. 21, 12 (2003).
21
Xue Y., et al., Human Y chromosome base-substitution mutation rate measured by direct sequencing in a deep-rooting pedigree. Curr. Biol. 19, 1453 (2009).
22
Ng S. B., et al., Exome sequencing identifies the cause of a mendelian disorder. Nat. Genet. 42, 30 (2010).
23
Olbrich H., et al., Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry. Nat. Genet. 30, 143 (2002).
24
Ng S. B., et al., Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272 (2009).
25
Choi M., et al., Proc. Natl. Acad. Sci. U. S. A. 106, 190961 (2009).
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Science
Volume 328 | Issue 5978
30 April 2010
30 April 2010
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Copyright © 2010, American Association for the Advancement of Science.
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Submission history
Received: 7 January 2010
Accepted: 5 March 2010
Published in print: 30 April 2010
Acknowledgments
This study was supported by the University of Luxembourg–Institute for Systems Biology Program and by these NIH grants: Center for Systems Biology GM076547 (L.H. and L.R.), RO1GM081083 (A.F.S. and G.G.), R01HL094976 and RZ1HG004749 (J.S.), RC2HG005608 (M.D. and J.S.), and R01HD048895 (M.B.). H. Tabor assisted with ethical review. J. Xing performed the principal components analysis. H. Mefford performed CNV analysis. A. Bigham and K. Buckingham evaluated candidate genes in unrelated individuals. D. Ballinger, A. Sparks, A. Halpern, and G. Nilsen assisted with sequencing and analysis. R. Bressler, S. Dee, and D. Mauldin assisted with bioinformatics. S. Ng and R. Qiu performed the capture array. S. Bloom obtained the resequencing data on the Illumina Genome Analyzer. M. Janer and S. Li performed Sequenom analysis. D. Cox commented on an early version of the manuscript. R. Durbin and D. Altshuler granted permission for our use of 1000 genomes SNP data. CGI employees (R.D. and K.P.) have stock options in the company. J.S. has consulted for CGI. L.H. is a scientific advisor to CGI and holds stock in the company. The dbGAP accessions can be found at www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000244.v1.p1 (accession phs000244.v1.p1).
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